Chemically induced hepatocarcinogenesis in the adult rat will be used as a model to test the hypothesis that new hepatocyte phenotypes arising during the premalignant phase of liver cancer development evole through two levels of altered proliferation control, each of which confers (a) survival advantage in cytotoxic environments induced by 2-acetylaminofluorene and (b) membership in cell lineages culminating in hepatocellular carcinoma. Preparative-scale techniques for the purification of proliferating and non-prolivering hepatocytes, arising in rat livers undergoind hepatocarcinogenesis, will be developed. Cell purification procedure will exploit variations in hepatocyte cell-membrane alloantigens observed during the cell cycle such that each cell population adheres differentially to antibody-coated substrata. Proliferating and non-proliferating hepatocytes will be purified from livers of Wistar-Furth and F344 rats administered four 4-week cycles of dietary 2-acetylaminofluorene or single injections of diethylnistrosamine or N-methyl-N-nitrosourea. The competitive efficiency of purified cell populations will be evaluated in genetic mosaic livers, constructed by quantitative transplants of parental cells to the livers of hybrid F344 x WF)F1 rats undergoing hepatocarcinogenesis induced by dietary 2-acetylaminoflurene. Colonies of proliferating hepatocytes of parental or F1 origin will be distinguished by immunohistochemical methods to localize alloantigens. Competition between cell populations purified from parental strains will be evaluated in F1 host rats containing transplants of mixtures of F344 and WF cells. The relation between the genotype of competitively efficient proliferating cells in parental/F1 mosaic livers and the genotype of resulting neoplastic nodules and hepatocellular carcinomas will be studied. With the use of discrete, purified heaptocyte populations, a formal correlation will be sought between the in vivo competitive efficiency and the capacity to resist cytolytic effects of toxic metablies of 2-acetylaminofluorene in vitro, the capacity to repair a class of aminofluorene-DNA adducts, and the capacity to serve as progenitor cells of hepatocellular carcinoma.